Studies suggest that cognitive impairment associated with normal aging is due to neuronal dysfunction rather than to loss of neurons or synapses. To characterize this dysfunction, molecular indices of synaptic integrity and energy metabolism were quantified in autopsy samples of cerebral cortex from healthy humans of different ages. During normal aging, dramatic declines could be demonstrated in levels of synaptic proteins involved in structural plasticity (remodeling) of pre- and post-synaptic (dendritic) elements. Alzheimer disease (AD) was associated with an additional 81% decrease in the level of drebrin, a protein regulating postsynaptic plasticity. AD also was associated with reduced activity and gene expression of mitochondrial and nuclear enzymes involved in oxidative phosphorylation, the process by which energy is produced in the form of ATP. Other evidence including positron emission tomography suggests that, in the early stages of AD, these reductions represent reversible downregulation of oxidative phosphorylation. Because mitochondrial DNA (mtDNA) transcription may be independently regulated to some extent, we set up an isolated mitochondrial transcription system from rat liver mitochondria to examine such regulation. The milieu of this system consisted of oxidizable substrates and constituents that maintained and supported transcription as seen in vivo. Rates of synthesis of mitochondrial (mt) transcripts were quantified using 32 P-UTP, and were shown to be stimulated by ADP but not ATP. Inhibition of mitochondrial respiration with rotenone completely abolished transcription. These results suggest that mitochondrial transcription is regulated by cellular energy demands, and provide a basis for examining coupling of neuronal activity to oxidative phosphorylation. The results are consistent with evidence in PC12 cells that mitochondrial transcription of subunits of cytochrome oxidase, the rate limiting enzyme in oxidative phosphorylation, is altered rapidly by intracellular changes in sodium and in the ATP/ADP ratio. - Mitochondria, Transcription, Synapses, Brain, Human, Alzheimer disease, Aging